Until now, β-hydroxybutyrate (BHB) has been known as a compound produced by the liver to be used as fuel. In a new study, researchers discovered that BHB also participates in another metabolic pathway; in this case, an enzyme called CNDP2 joins BHB to amino acids; furthermore, the most abundant BHB-amino acid, N-β-hydroxybutyryl phenylalanine (BHB-Phe), can influence body weight and metabolism in animal models.
Mammals have evolved complex nutrient-responsive pathways that link the availability of external energy sources to internal metabolic homeostasis.
These pathways involve changes to cellular energy metabolites, which function both as metabolic fuels and as downstream effectors.
A key example is BHB, a ketone body whose levels rise during periods of low carbohydrate availability, such as during starvation, intermittent fasting, or with consumption of a ketogenic diet.
In the new research, Baylor College of Medicine Professor Yong Xu and colleagues aimed to investigate how BHB-Phe — the most abundant BHB-amino acid — influences feeding behavior and body weight in mice.
“We know that groups of neurons in the brain regulate feeding behavior, so we mapped the entire brain to determine which areas were activated by BHB-Phe,” Professor Xu said.
“We found that BHB-Phe activates neural populations in the hypothalamus and brainstem, and this suppresses feeding and reduces body weight.”
“In contrast, mice genetically modified to not produce CNDP2 and therefore lack BHB-Phe, ate more and gained weight.”
Interestingly, the CNDP2 enzyme that produces BHB-Phe also produces a related compound called Lac-Phe, previously discovered by the team.
“Lac-Phe is a compound in the blood that is produced during exercise and can reduce food intake and obesity in mice,” Professor Xu said.
“But do Lac-Phe and BHB-Phe mediate their common effects by activating the same neurons in the brain?”
“Our analyses showed that only a small proportion of neurons…
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